Durable responses to immunotherapy in dMMR/MSI-H metastatic colorectal cancer patients with poor performance status.

Abstract

76 Background: Immune checkpoint blockers (ICBs) are front-line therapy for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Poor ECOG performance status (PS) is widely recognized as a negative prognostic factor in patients receiving ICBs and other systemic therapies, often leading physicians to withhold treatment in this clinical context. We aimed to assess the effect of ECOG PS on patient outcomes in dMMR/MSI-H mCRC. Methods: An international multicenter retrospective cohort study of ICBs-naïve dMMR/MSI-H mCRC patients who received ICBs between 2014–2024. Exposure variables included best treatment response (CR, PR, SD or PD); and patient characteristics including line of treatment, RAS/BRAF status, single-agent versus doublet ICBs, and metastatic sites. The main outcome was overall survival. Kaplan-Meier analysis was used to analyze the association of best treatment response with overall survival according to ECOG PS of 2-3 and 0-1. Univariate Cox proportional hazard regression model was used to analyze the effect of all exposure variables on overall survival. Results: The study cohort included 51 dMMR/MSI-H mCRC patients with ECOG PS of 2-3 and 633 patients with ECOC PS of 0-1 that were treated with ICBs. Median follow-up time was 35.3 months (IQR 23.9 – 54.9) and 49.9 months (IQR 46.7-53.8), respectively. For patients with ECOG PS of 2-3 ORR and DCR rates were 37.3% and 60.8%. The median overall survival (mOS) was 14.4 months - not reached for those who achieved CR/PR and 1.7 months in those whose best response was PD. For patients with ECOG PS of 0-1, mOS was not reached, and ORR was 60.0%. Conclusions: Patients with dMMR/MSI-H mCRC and ECOG PS 2-3 derive durable benefit from ICBs, mainly among those who achieved CR/PR, and should therefore be considered candidates for this therapy.